Achieving cross-coupling reactions of fatty amide reduction radicals via iridium-photorelay catalysis and other strategies

(Press-News.org) Professor Pei-Qiang Huang's research group at Xiamen University recently reported the first reduction-cross-coupling reaction of aliphatic tertiary amides with 4-cyanopyridine via iridium and photoredox tandem catalysis. This method is based on the formation of imineonium through iridium-catalyzed hydrosilylation and acid catalysis, followed by tandem photocatalysis to generate two radicals (C,N,N trialkyl α-amino radical and stable 4-cyano-1,4-dihydropyridine radical) which then undergo a cross-coupling reaction. The reaction exhibits excellent chemoselectivity, enabling gram-scale reactions with extremely low catalyst loadings, and the products can be converted in one step to partially and fully saturated α-nitrogen-substituted amines. These characteristics make this method promising for applications in organic synthesis, natural products, and pharmaceuticals. The article was published as an open access Research Article in CCS Chemistry, the flagship journal of the Chinese Chemical Society.

Background information:

Alpha-substituted fatty amines and nitrogen-containing heterocycles are widely found in numerous bioactive natural products, pharmaceutical molecules, and agrochemicals. A recent analysis of small molecule drugs approved by the US FDA from 2013 to 2023 shows that 82% of the drug molecules contain at least one nitrogen heterocycle structure, with pyridine and its saturated form piperidine being the most and second most common nitrogen heterocycle structures, respectively. Therefore, combining α-substituted fatty amine structural units with pyridinyl, piperidinyl, and other groups constitutes a highly valuable synthetic target in new drug development.

The synthesis of functionalized amines from structurally stable and abundant amides has attracted considerable attention in recent years. However, the photocatalytic reductive functionalization of amides can only be achieved on N-arylbenzamide substrates. The photocatalytic reductive functionalization of C,N,N-trialkylamides faces several challenges.

Highlights of this article:

1. This method successfully solved the key challenge of catalytic generation of C,N,N-trialkyl α-amino radicals and their cross-coupling in aliphatic amides. By promoting the formation of an imine ion intermediate via TfOH and combining it with a proton-coupled electron transfer strategy, electrophilic and long-lived 4-cyano-1,4-dihydropyridine radicals are generated under visible light catalysis. This achieves polar-matched radical-radical coupling with nucleophilic C,N,N-trialkyl α-amino radicals, providing an efficient α-position modification pathway for aliphatic amides that are traditionally difficult to directly functionalize.
2. It exhibits good functional group tolerance and synthetic practicality, making it suitable for the late-stage modification of complex molecules. This method demonstrates good compatibility with various functional groups such as alkenyl, halogen (bromine, chlorine), trifluoromethyl, cyano, and ketone groups, and has been successfully applied to the late-stage pyridylation modification of amide derivatives of various bioactive molecules, providing a powerful tool for the structural diversification of drug molecules and natural products.
3. Gram-scale reaction and one-pot conversion of products were achieved, demonstrating good scalability and synthetic flexibility. The reaction can be scaled up to 10 mmol with a low iridium catalyst loading of 0.001 mol%, and the target product is obtained in good yield.

Summary and Outlook:

This study developed a reductive cross-coupling reaction catalyzed by iridium catalysis and photoredox synergy, achieving the direct coupling of aliphatic tertiary amides with 4-cyanopyridine, and efficiently synthesizing α-pyridin-4-yl alkylamines. The core innovation of this reaction lies in the polarity-matched cross-coupling of two free radicals (C,N,N-trialkyl α-amino radical and stable 4-cyano-1,4-dihydropyridine radical) generated by photocatalysis. This method exhibits good compatibility with various functional groups, including alkenyl, halogen (bromine, chlorine), trifluoromethyl, cyano, and ketone groups, and has been successfully applied to the late-stage pyridylation modification of amide derivatives of various bioactive molecules. Furthermore, the reaction can be carried out on a gram-scale with extremely low catalyst loading, and the product can be converted in one step to partially and fully saturated α-nitrogen-substituted amines. These characteristics make this method promising for applications in organic synthesis, natural products, and pharmaceuticals.

This research was recently published in CCS Chemistry. Professor Pei-Qiang Huang of the College of Chemistry and Chemical Engineering at Xiamen University is the corresponding author, Zheng-Yun Weng, a doctoral student at Xiamen University, is the first author, and Yu-Qing Li is the second author. This work was supported by the National Natural Science Foundation of China.

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About the journal: CCS Chemistry is the Chinese Chemical Society’s flagship publication, established to serve as the preeminent international chemistry journal published in China. It is an English language journal that covers all areas of chemistry and the chemical sciences, including groundbreaking concepts, mechanisms, methods, materials, reactions, and applications. All articles are diamond open access, with no fees for authors or readers. More information can be found at https://www.chinesechemsoc.org/journal/ccschem.

About the Chinese Chemical Society: The Chinese Chemical Society (CCS) is an academic organization formed by Chinese chemists of their own accord with the purpose of uniting Chinese chemists at home and abroad to promote the development of chemistry in China. The CCS was founded during a meeting of preeminent chemists in Nanjing on August 4, 1932. It currently has more than 120,000 individual members and 184 organizational members. There are 7 Divisions covering the major areas of chemistry: physical, inorganic, organic, polymer, analytical, applied and chemical education, as well as 31 Commissions, including catalysis, computational chemistry, photochemistry, electrochemistry, organic solid chemistry, environmental chemistry, and many other sub-fields of the chemical sciences. The CCS also has 10 committees, including the Woman’s Chemists Committee and Young Chemists Committee. More information can be found at https://www.chinesechemsoc.org/.

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